Abstract: Non-small cell lung cancers (NSCLC), which account for 85% of all lung cancers, are very heterogeneous tumors. Despite advances in understanding NSCLC biology and developing therapies, the prognosis for NSCLC remains poor with low survival rates with minority populations. Only 0.6 percent of African Americans survive beyond 18 months after Tyrosine Kinase therapy. This health disparity in lung cancer makes this proposal responsive to U54 RCMI program. There is an urgent need of therapeutic agents as an alternative to TKIs or drugs that can chemo-sensitize TKI-resistant NSCLC cells. CARP-1 functional mimetic (CFM) compounds are a novel class of anticancer agents that show activity against multiple cancer cell lines including breast, lung, and medulloblastoma. However, the role of CARP-1 in TKI- induced apoptosis or resistance reversal pathways has not been explored previously. Our preliminary data suggest high concentration of CFMs, especially, CFM4.16 and CFM4.17, directly attenuate growth of the parental and chemo-resistant NSCLC cells, and at low concentrations it restores the chemo- sensitivity of TKIs. CFMs activate p38/JNKs while inhibiting pro-survival cMet and Akt kinases in both the parental and resistant NSCLC cells as well as NSCLC PDX tumoroids. CFMs inhibit NSCLC cell migration and invasion, while CARP-1 depletion blocks cell growth inhibition by CFMs. Further, CFMs enhance the effectiveness of erlotinib on 3D spheroid inhibition as well as different clones of erlotinib resistant cells. Therefore, modulation of CARP-1 and its apoptosis signaling could be a novel mechanism for treating NSCLCs. This project is designed to evaluate CFM4.16 and CFM4.17 as potential therapies for NSCLC based on the expected mechanism of restoring TKI sensitivity in NSCLC cells that gain resistance to TKIs over time. The proposed work is based on the hypothesis that a) CFMs have anti-NSCLC activity (that can be exploited therapeutically), and b) CFMs restore TKI chemosensitivity in TKI-resistant NSCLC. Nanolipid formulations (NLFs) of CFM lead compounds (CFM4.16 and CFM4.17) are expected to maximize our success in TKIs resistant NSCLC. Aim 1. To develop and characterize a nanolipid formulation (NLF) of CFM-4.16 and CFM-4.17 for oral delivery. Aim 2. To evaluate In vivo anticancer efficacy of optimized CFM NLF formulations of 4.16 and 4.17 (from specific aim 1) alone and in combination with Erlotinib. Aim3. To elucidate the mechanism of action of CFMs induced cytotoxicity and chemo-sensitization in patient-derived xenograft (PDX) model. This high impact study is expected to lay the groundwork for a future R01 application for further evaluating this approach with other TKIs and possible clinical trials, with the ultimate outcome of improving NSCLC treatment outcomes.